Human Molecular Genetics Advance Access published online on June 22, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh189
© 2004 by Oxford University Press
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1 Departments of Pediatrics, Medicine and the Comprehensive Cancer Center, UCSD School of Medicine
* To whom correspondence should be addressed. E-mail: awynshawboris{at}ucsd.edu.
Reactive oxygen species (ROS) are important endogenous etiological agents for DNA damage, and ROS perform critical signaling functions in apoptosis, stress responses and proliferation. The correlation between a lower incidence of cancer in people that consume a diet high in naturally occurring antioxidants and the observed increased ROS in cancerous tissues suggest that antioxidants may be used in cancer chemoprevention. We tested this hypothesis by determining whether the well-described nitroxide antioxidant, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), acts as a chemopreventative agent in Atm mutant mice, a model of the human cancer prone syndrome ataxia-telangiectasia (AT). Tempol administered continuously via the diet after weaning resulted in an increased lifespan of these mice by prolonging the latency to thymic lymphomas. Tempol treatment reduced ROS, restored mitochondrial membrane potential, reduced tissue oxidative damage and oxidative stress, consistent with antioxidant effects. In addition, this nitroxide lowered weight gain of tumor prone mice without changes in food intake, metabolism, or activity level and exhibited an anti-proliferative effect in vitro. Thus, Tempol acts as a novel chemopreventative agent in this mouse model of a human cancer prone syndrome, associated with broad antioxidant effects.
Article
Cancer chemoprevention by the antioxidant Tempol in Atm-deficient mice
2 Genetic Disease Research Branch, NHGRI, NIH; Salk Institute, La Jolla, CA
3 Departments of Pediatrics, Medicine and the Comprehensive Cancer Center, UCSD School of Medicine; Department of Surgery, Taku Hospital, Saga, Japan
4 Genetic Disease Research Branch, NHGRI, NIH
5 Radiation Biology Branch, NCI
6 Departments of Pediatrics, Medicine and the Comprehensive Cancer Center, UCSD School of Medicine; Genetic Disease Research Branch, NHGRI, NIH; University of California, San Diego, School of Medicine, 9500 Gilman Drive, Mail stop 0627, La Jolla, CA 92093-0627
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